PEG drugs: an overview
Introduction
No discussion of PEG drugs would be complete without an introduction to the beginnings of PEG conjugation. The advent of PEG chemistry began in 1977 with the findings of Abuchowski et al. [1] that the alteration of immunological properties of bovine serum albumin (BSA) had been achieved by the covalent attachment of poly(ethylene) glycol, more conveniently referred to as PEG. These researchers soon demonstrated that conjugating PEG (PEGylation) to E. coli l-asparaginase, an anticancer enzyme [2], produced a PEG–l-asparaginase that was now essentially non-immunogenic. This compound was further developed clinically and is currently sold by Enzon, using the trade name Oncaspar®.
Probably, the most important feature of PEG modification is that it greatly extends the half-life (t1/2) of most proteins, and results in a greatly increased plasma presence. This can be attributed, in part, to the increase in molecular weight of the conjugate beyond the limits of renal filtration; reduced proteolysis of the PEG-conjugated enzyme also appears to be a factor. Usually, the specific activity of the protein declines after modification, but this is more than compensated for by the greater area under the pharmacokinetic (PK) curve, and increased water solubility is an additional benefit. Most PEG conjugates (of both high and low molecular weight) have been produced by first activating PEG at the OH termini of either diol or mono methoxy PEG. Examples of activated mPEGs are provided in Table 1. A more recent modification is provided by branched chain PEG which provides an umbrella like covering (U-PEG, PEG 2) [3], [4] and has demonstrated utility in protein conjugates.
Section snippets
Permanently bonded PEG-drugs
In contrast to the voluminous work on PEGylated proteins, the paucity of information in the literature relating to PEG-low molecular weight (lmw) organic molecules and drugs prior to 1994 is striking. Several in vivo biological studies of PEG-drugs did not reflect the initial in vitro results observed [5], [6]. These puzzling findings were not resolved, and apparently interest waned without the emergence of a clinically relevant candidate. Biologically active protein conjugates were synthesized
Low molecular weight (lmw<20 000) PEG prodrugs
Prodrug design comprises an area of drug research that is concerned with the optimization of drug delivery. A prodrug is a biologically inactive derivative of a parent drug molecule that usually requires an enzymatic transformation within the body in order to release the active drug, and has improved delivery properties over the parent molecule [24], [25], [26], [27]. PEG prodrugs of highly insoluble anticancer agents should be especially advantageous since the solubility of the prodrug will
Benzyl elimination (BE)
Until recently there have been very few published methods available for the practical synthesis of PEG amino prodrugs. While most amine drugs can be solubilized as acid salts, their rate of renal excretion is high. When converted to neutral small prodrug species, the ability to form salts is lost, and solubility may again become problematic. This is not the case for PEG–drug conjugates, where PEG confers water solubility on insoluble small organic compounds without the need for forming salts.
Future directions
Another proposed use may very well be in the making of combinations of ‘PEG-hybrids,’ i.e., proteins first conjugated with rPEG to block active sites, and then with a permanently bonded PEG species such as SC-PEG. Removal of the rPEGs can easily be done during processing, leaving a PEG protein with many available active sites as the product which, hopefully, will demonstrate high specific activity. A similar approach has been initiated by Tsunoda et al. [51] for TNF-α using the small reactive
Concluding remarks
Why use PEG as the carrier for polymer therapeutics?
PEG is essentially non-toxic; PEG conjugated proteins have already been approved for human use; PEG can be obtained with low polydispersity, is easily activated for conjugation, and PEG is relatively inexpensive for large scale processes.
PEG chemistry has experienced a resurgence in the last 5 years that in large part may be attributed to the use of hmw PEG conjugates. The successful application of α-interferon PEGylation by Schering-Plough
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